A large body of evidence has shown that circular RNAs (circRNAs) play a significant role in the progression of some malignant cancers, including hepatocellular carcinoma (HCC). However, the complex mechanism of circRNAs in hepatocellular carcinoma has not been clarified.We identified circRNAs by microarray analysis and quantitative real-time polymerase chain reaction (RT-qPCR). We also carried out bioinformatics analysis, luciferase reporter assays, and RNA pull-down assays to define the relationship between microRNA (miR)-543 and circARPP21. Through silencing and overexpression of circARPP21, we investigated the effects of circARPP21 on proliferation, migration, and invasion abilities of HCC cells in vitro and in vivo.In this study, we found that a novel circRNA, circARPP21 (hsa_circ_0123629), exerts a strong effect on HCC progression. Reduced expression of circARPP21 in HCC patients is correlated with larger tumor size, higher tug-lymph node metastasis (TNM) stage, and poor prognosis as indicated by elevated levels of alpha-fetoprotein (AFP). Conversely, higher expression of circARPP21 can increase leukemia inhibitory factor receptor (LIFR) expression by sponging miR-543. Finally, overexpression of miR-543 can reverse the anti-proliferation and anti-metastasis effects of circARPP21.The circARPP21/miR-543/LIFR axis suppresses the proliferation, invasion, and migration of hepatocellular carcinoma cells. In addition, circARPP21 can serve as a biomarker in HCC, thus offering a potential new approach to HCC therapy.